Allergy or hypersensitivity of the immune system in its different forms affects more than 20% of the human population. Furthermore, man is a highly susceptible species to anaphylaxis. After sensitization with an allergen, a second exposure elicits constriction of the bronchioles, in some cases resulting in death from asphyxia. This allergic reaction is mediated by allergen-specific antibodies, mostly of the IgE class. The antibodies can be directed against a variety of antigens, such as molecules from pollen, fungi, food, house dust mite, hymenoptera venoms or animal danders. The aggregation of mast cell and basophil high-affinity IgE receptors by IgE and antigen causes the release of mediators and cytokines, including heparin, eosinophil and neutrophil chemotactic factors, leukotrienes and thromboxanes.
While our understanding of the inflammatory process in allergic reactions and asthma has improved remarkably over the past decade, our ability to control them remains modest. The prevalence of asthma in industrialized countries has increased by almost 80% since 1980. The specific causes for this increase in prevalence are not clear, but the rise in prevalence may be due in part to the absence of effective therapies that reverse the progression of, or cure, this disease. Currently available therapies, such as inhaled corticosteroids, antileukotrienes or 2-agonists, focus rather on symptom relief, reduction or neutralization of effector molecules and inflammatory mediators. This approach, while effective for acute disease and for relieving symptoms, however, has limited long term salutary effects, since the environmental factors that cause and precipitate asthma are not eliminated, and patients redevelop symptoms of asthma when these medications are discontinued.
The profile of cytokines produced by CD4+ T cells during an immune response determines the nature of effector functions which develop and regulates the outcome of an immune response. Production of IL-2 and IFN— during Th1-dominated responses is associated with vigorous cell-mediated immunity, the induction of IgG2a and inhibition of IgE synthesis, and with resistance to intracellular pathogens. In contrast, the production of IL-4, IL-5 and IL-10 during Th2-dominated responses is associated with humoral immunity and protection from autoimmune pathology. Overproduction of Th2-cytokines by allergen-specific CD4+ T cells can result in the development of allergic disease and asthma.
One approach to allergic diseases is immunotherapy. Immunotherapy has proven to be effective when used properly, and it is hoped that advances in immunologic intervention will further improve the efficacy. Modification of allergens, and the use of cytokines, may succeed in shutting down production of specific IgE and thus cure symptomatic allergies. Alternative approaches have attempted to use cytokines to shift the immune response. IL-12, a heterodimeric cytokine produced by macrophages and dendritic cells, is potent in driving the development of Th1 cytokine synthesis in naive and memory CD4+ T cells. However, several in vivo studies have demonstrated that rIL-12 as an adjuvant, while enhancing IFN— synthesis, in some cases paradoxically also increases IL-4 and IL-10 synthesis in antigen primed CD4+ T cells.
In contrast with drug therapy, immunotherapy could result in long-term, favorable alteration of the patient's immunologic status. Immunological changes that have been described after immunotherapy include an initial rise in specific serum IgE, followed by a fall, and a rise in specific IgG (“blocking antibody”). Immunotherapy leads to a reduction in mediator release from mast cells in vitro, alterations in lymphocyte subsets, and a downregulation of IL-4 production from T cells (Secrist et al. (1993) J. Exp. Med. 178: 2123–2130). Several studies have shown a reduction in inflammation and a decrease in bronchial hyper-responsiveness after immunotherapy.
This immunotherapy strategy, however, which might cure asthma and reduce its prevalence, is feasible only if potent therapies are developed that reverse ongoing airway hyperreactivity and reverse the ongoing allergic inflammatory process, which plays a critical role in the pathogenesis of asthma (Martinez et al. (1995) New Eng. J. Med. 332:133–8). Conventional allergen immunotherapy, while capable of reducing specific IL-4 production, requires multiple injections over several years time and is associated with frequent failure (Creticos (1992) JAMA 268:2834–9). Experimental methods described up to now, for example using IL-12 as adjuvant (Kim et al. (1997) J. Immunol. 158:4137–44), or immunization with plasmids containing the cDNA for allergens (Hsu et al. (1996) Nature Medicine 2:540–544), while effective in preventing the development of Th2-dominated immune response, have not been shown to reverse ongoing airway hyperreactivity.
Current therapy for asthma aims to suppress inflammation with inhaled corticosteroids, sodium cromoglycate, or nedocromil sodium, all of which interfere with the cellular and cytokine interactions by diverse mechanisms, but do not address the initiating event in allergic asthma. By altering the immune response to allergen, it may be possible to control the trigger of asthma, and of other allergic disorders.
Relevant Literature
Listeria monocytogenes, a gram positive, intracellular, facultative bacterium, elicits a strong classical cell-mediated immune response, characterized by the presence of potent antigen-specific CD8 killer cells. Listeria rapidly activates innate immunity and induces high levels of IL-12. This results in high IFN— production in NK cells and stimulates the induction of strongly polarized Th1 CD4 T cells, as discussed in Hsieh et al. (1993). Science 260:547–549. The immune response against Listeria is discussed in Fauve, U.S. Pat. No. 4,180,563; in DeKruyff et al. (1997) J. Immunol. 158:359–366; Miller et al. (1996) Ann. N.Y. Acad. Sci. 797:207–227; and others.
IL-12 and its biological activity is characterized in Okamura et al. (1995) Nature 378:88–91. The role of IL-12 in suppressing IgE synthesis is discussed in Kiniwa et al. (1992) J. Clin. Invest. 90:262–266. IL-12 inhibition of the production of IL-4 and IL-10 is disclosed in Marshall et al., (1995) J. Immunol. 155:111–117. The combined activity of IL-12 and IL-18 on IgE synthesis is disclosed by Yoshimoto et al. (1997) Proc. Natl. Acad. Sci. USA, 94:3948–3953.
Weber (1997) JAMA 278(22):1881–1887 reviews immunotherapy with allergens. Bousquet et al. (1991) J. Aller. Clin. Immunol. 99:43–53 provide evidence for immunotherapy efficacy. Soderlund et al. (1997) Immunol Lett 57:(1–3):177–181 discuss allergen induced cytokine profiles in type I allergic individuals before and after immunotherapy. Nelson (1997). Allergy Asthma Proc 18(3):157–162; and Creticos et al. (1996) N Engl J Med 334(8):501–506, review the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. Gavett et al. (1995) J. Exp. Med. 182:1527–1536 disclose a role for IL-12 in asthma immunotherapy.